A transdermal patch of agomelatine

Abstract

The present application provides a transdermal patch of agomelatine and a preparation method thereof. Specifically, the transdermal patch of agomelatine comprises (a) a backing layer, (b) an adhesive matrix layer and (c) a protective layer, wherein the adhesive matrix layer contains agomelatine and an adhesive matrix, and optionally further comprises a penetration enhancer. The transdermal patch of agomelatine prepared by the method has a fast transdermal absorption rate, a high transdermal absorption amount, and the characteristics of stability, high efficiency, good uniformity and low irritation, and the preparation method is simple.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and mainly relates to transdermal patches containing agomelatine, their pharmaceutical uses, and preparation methods. Background Technology

[0002] Depression is a common, relapsing, and highly disabling mental illness. Based on findings from research on the pharmacological mechanisms of antidepressants, a hypothesis has been proposed that depression is caused by dysfunction of the monoamine neurotransmitter system. The main mechanism of action of existing antidepressants is the regulation of this system. Although newer antidepressants have made significant improvements in safety and tolerability, they still suffer from slow onset of action, poor efficacy in some patients, and potential adverse reactions during long-term treatment, indicating significant room for improvement in treatment.

[0003] Agomelatine is a novel antidepressant, a melatonin receptor agonist and serotonin 2C (5-HT2C) receptor antagonist. It is the world's first melatonin-based antidepressant, a naphthalene derivative of melatonin with the indole ring replaced by a naphthalene nucleus, making it more metabolically stable than melatonin. It is a selective and specific agonist of the hypothalamic melatonin receptor, while also exhibiting weak competitive antagonistic activity against 5-HT receptors, displaying a novel pharmacological characteristic of dual action as a melatonin receptor agonist and selective 5-HT antagonist. It mimics the effects of melatonin while possessing a unique mode of action, making it a promising candidate drug for treating circadian rhythm disorders such as sleep disorders / depression.

[0004] Agomelatine is a white or off-white crystalline powder, chemically named N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide, with the molecular formula C2. 15 H 17 NO2, molecular weight 243.3, chemical structural formula is:

[0005]

[0006] Agomelatine is currently only available in oral tablet form, taken once daily at bedtime. However, oral administration of agomelatine results in low bioavailability in humans, with significant inter-individual and intra-individual variability. Due to the limited dosage form, there is a pronounced first-pass effect in the liver and gastrointestinal disruption, resulting in a final bioavailability of only 3%–4% for oral tablets. Therefore, it is necessary to improve oral tablets to develop dosage forms with a constant release rate, low hepatotoxicity, and high bioavailability.

[0007] Patent CN103830206A discloses a transdermal drug delivery formulation of agomelatine with a three-dimensional network structure and its preparation method. The formulation consists of a backing layer, a drug-loaded three-dimensional network structure coated on the backing layer, and an anti-adhesive layer laminated thereon. This invention not only effectively achieves sustained transdermal drug delivery for a longer period, maintaining a constant blood drug concentration, but also exhibits rapid transdermal absorption and high transdermal absorption capacity, demonstrating stability and high efficiency. However, this technology requires the use of nano-silica as a drug carrier to form a three-dimensional network structure, and then using this three-dimensional network structure system in the preparation of transdermal patches. The method is too complex, and reproducibility is difficult to guarantee.

[0008] Patent CN110151735A discloses an agomelatine transdermal patch and its preparation method. The preparation steps are as follows: micronizing a specific crystal form of agomelatine crystals; dispersing it in a mixture of fucosterol, octanol, 2-pyrrolidone, and isopropanol; and coating it onto a high-molecular-weight pressure-sensitive adhesive to obtain the patch. This invention achieves rapid transdermal absorption of agomelatine, high transdermal absorption capacity, and features stability, high efficiency, good uniformity, and low irritation, which is beneficial for its widespread clinical application. However, this technology requires micronizing the API first, which may cause API degradation and generate impurities. Moreover, considering the low yield of micronization, the economic efficiency is low.

[0009] Patent WO2016109483A1 discloses a transdermal patch containing agomelatine, delivered via an enhancer selected from isopropanol and ethanol. This technology produces a "reservoir-type" transdermal patch, which suffers from poor stability, reproducibility, and uniformity, posing a risk of dosage leakage and presenting significant challenges for industrialization.

[0010] The advantages of transdermal patches include avoiding the first-pass metabolism in the liver, reducing gastrointestinal irritation, minimizing toxic side effects, lowering drug dosage, and improving patient compliance. Formulating agomelatine into a transdermal patch, bypassing gastrointestinal degradation and the first-pass metabolism in the liver, can effectively address the low bioavailability of oral tablets and improve patient compliance. However, existing formulations are either complex and difficult to reproduce, or suffer from poor formulation stability, affecting drug safety. Therefore, there is an urgent clinical need for a reproducible and safe transdermal patch for agomelatine. Summary of the Invention

[0011] The purpose of this invention is to provide an agomelatine transdermal patch with stable drug release performance, comprising (a) a backing layer, (b) an adhesive matrix layer and (c) a protective layer, wherein the (b) adhesive matrix layer contains agomelatine and an adhesive matrix.

[0012] In a preferred embodiment of the present invention, in the adhesive matrix layer (b), the weight percentage of the active pharmaceutical ingredient agomelatine is 1-15% and the weight percentage of the adhesive matrix is ​​75-95% based on the total weight of the adhesive matrix layer.

[0013] In a more preferred embodiment of the present invention, agomelatine is mixed in the adhesive layer in a dissolved state, and the content is 5 to 15% of the total weight of the adhesive matrix layer, preferably 10 to 15%, 8 to 12%, and more preferably 10 to 12%.

[0014] In a more preferred embodiment of the present invention, the adhesive matrix content is 75-95% by weight, preferably 80%-90%, based on the total weight of the adhesive matrix layer.

[0015] In a preferred embodiment of the present invention, the adhesive matrix is ​​a non-aqueous adhesive.

[0016] In a more preferred embodiment of the present invention, the adhesive matrix used in the adhesive matrix layer of the patch of the present invention is one or more of polyisobutylene, silicone, acrylic, polyurethane, natural rubber, and synthetic rubber, preferably one or a combination of styrene-isoprene-styrene block copolymer (SIS), polyamide, polyurethane, polyisobutylene pressure-sensitive adhesive, silicone pressure-sensitive adhesive, acrylate pressure-sensitive adhesive, and hot melt pressure-sensitive adhesive, more preferably acrylate pressure-sensitive adhesive and / or styrene-isoprene-styrene block copolymer.

[0017] In a preferred embodiment of the present invention, the thickness of the adhesive matrix layer is 10-150 μm, preferably 20-80 μm, and more preferably 40-65 μm.

[0018] In a preferred embodiment of the present invention, the adhesive matrix layer may also contain one or more other pharmaceutically acceptable excipients such as penetration enhancers, antioxidants, surfactants, fillers, flavoring agents, and colorants.

[0019] In a more preferred embodiment of the invention, the total weight percentage of other pharmaceutically acceptable excipients does not exceed 15%.

[0020] The penetration enhancer used in this invention can be one or more of the following: sulfoxides, pyrrolidones, amides, fatty acids and their esters, surfactants, alcohols, polyols, terpenes, and phospholipids, such as propylene glycol, oleic acid, stearic acid, isostearic acid, lactic acid, lauric acid, polyethylene glycol, isopropyl myristate, isopropyl palmitate, decyl methyl sulfoxide, dimethylacetamide, and triglycerides. The penetration enhancer content is 0-15% (by weight), preferably 1-8% (by weight), and more preferably 2-6% (by weight), based on the total weight of the adhesive matrix layer.

[0021] The antioxidants used in this invention are selected from butylated hydroxytoluene, tert-butyl-p-hydroxyanisole, propyl gallate, ascorbic acid, and sodium metabisulfite. The antioxidant content is 0-2% (by weight) based on the total weight of the adhesive matrix layer, preferably 0-1% (by weight).

[0022] The fillers used in this invention can be selected from silica, titanium dioxide, metal stearate, calcium carbonate, polyvinyl ketone, and acrylic resin. The filler content is 0-1% (by weight) based on the total weight of the adhesive matrix layer.

[0023] In a more preferred embodiment of the present invention, when the adhesive matrix is ​​selected from silicone, silicone pressure-sensitive adhesive is preferred. More preferably, the weight percentage of agomelatine is 5-15% and the weight percentage of adhesive is 85%-95% based on the total weight of the adhesive matrix layer.

[0024] In a more preferred embodiment of the invention, when the adhesive matrix is ​​selected from acrylics, an acrylic pressure-sensitive adhesive is preferred; more preferably, based on the total weight of the adhesive matrix layer, agomelatine accounts for 5-15% by weight, the adhesive matrix accounts for 75%-87% by weight, the penetration enhancer accounts for 2-10% by weight, and the antioxidant accounts for 0-2% by weight; even more preferably, based on the total weight of the adhesive matrix layer, agomelatine accounts for 10-15% by weight, and the adhesive accounts for 75%-90% by weight. The weight percentage of the penetration enhancer is 2-8%, and the weight percentage of the antioxidant is 1-2%. More preferably, based on the total weight of the adhesive matrix layer, the weight percentage of agomelatine is 10-15%, the weight percentage of acrylate pressure-sensitive adhesive is 75%-85%, the weight percentage of isopropyl myristate is 2%-4%, the weight percentage of polyethylene glycol is 0-2%, the weight percentage of lactic acid is 1%-3%, the weight percentage of oleic acid is 1%-2%, and the weight percentage of dimethylacetamide is 1%-2%.

[0025] In a more preferred embodiment of the present invention, the acrylate pressure-sensitive adhesive is selected from copolymers containing 2-ethylhexyl acrylate, preferably one or more of DURO-TAK 2287, DURO-TAK 4098, DURO-TAK 2510, DURO-TAK 2516, DURO-TAK 2074, and DURO-TAK 2677; more preferably one or more of DURO-TAK 387-2287, DURO-TAK 87-4098, DURO-TAK 387-2516, DURO-TAK 87-2074, DURO-TAK 87-2677, DURO-TAK 387-2510, or DURO-TAK 87-2510; further preferably it contains at least DURO-TAK 2287, and optionally also contains DURO-TAK 4098, DURO-TAK 2510, and DURO-TAK 2677. 2516, DURO-TAK 2074 and / or DURO-TAK 2677; further preferably including at least DURO-TAK 4098, optionally also including DURO-TAK 2287, DURO-TAK 2510, DURO-TAK 2516, DURO-TAK 2074 and / or DURO-TAK 2677; further preferably including at least DURO-TAK 2516, optionally also including DURO-TAK 2287, DURO-TAK 2510, DURO-TAK 4098, DURO-TAK 2074 and / or DURO-TAK 2677; further preferably including at least DURO-TAK 2074, optionally also including DURO-TAK 2287, DURO-TAK 2510, DURO-TAK 4098, DURO-TAK 2287, DURO-TAK 2510, DURO-TAK 2098, DURO-TAK 2074 and / or DURO-TAK 2677. 2516 and / or DURO-TAK 2677; the most preferred combination is DURO-TAK 2287 and DURO-TAK 4098 or DURO-TAK 2516 and DURO-TAK 2074.

[0026] In a more preferred embodiment of the present invention, the penetration enhancer is selected from isopropyl myristate, lactic acid, a two-component combination of isopropyl myristate and lactic acid, a two-component combination of triglyceride and lactic acid, a three-component combination of isopropyl myristate, lactic acid and dimethylacetamide, a three-component combination of isopropyl myristate, lactic acid and polyethylene glycol, a four-component combination of isopropyl myristate, oleic acid, lactic acid and dimethylacetamide, or a five-component combination of isopropyl myristate, oleic acid, lactic acid, polyethylene glycol and dimethylacetamide.

[0027] In a more preferred embodiment of the present invention, the weight percentages of each component in the adhesive matrix layer of the patch are as follows:

[0028] materials percentage(%) Agomelatin 10％-15％ Acrylic pressure-sensitive adhesive 75％-85％ methacrylate alkyl ester copolymer 1％-5％ Penetration enhancer 2％-10％

[0029] Preferably, the weight percentages of each component in the adhesive matrix layer of the patch are as follows:

[0030] materials percentage(%) Agomelatin 10％-15％ Acrylic pressure-sensitive adhesive 70％-85％ methacrylate alkyl ester copolymer 1％-3％ Isopropyl myristate 2％-4％ polyethylene glycol 0-2％ lactic acid 1％-3％ Oleic acid 1％-2％ dimethylacetamide 1％-2％

[0031] In a more preferred embodiment of the present invention, the weight percentages of each component in the adhesive matrix layer of the patch are as follows:

[0032] materials percentage(%) Agomelatin 5％-15％ DURO-TAK 387-2287 70％-80％ DURO-TAK 87-4098 5％-15％ Isopropyl myristate 2％-4％ dimethylacetamide 1％-2％ lactic acid 1％-2％ .

[0033] In a more preferred embodiment of the present invention, the weight percentages of each component in the adhesive matrix layer of the patch are as follows:

[0034] materials percentage(%) Agomelatin 5％-15％ DURO-TAK 387-2516 70％-80％ DURO-TAK 87-2074 5％-15％ Isopropyl myristate 2％-4％ dimethylacetamide 1％-2％ lactic acid 1％-2％ .

[0035] In a more preferred embodiment of the present invention, the weight percentages of each component in the adhesive matrix layer of the patch are as follows:

[0036]

[0037]

[0038] In a more preferred embodiment of the present invention, the weight percentages of each component in the adhesive matrix layer of the patch are as follows:

[0039] materials percentage(%) Agomelatin 10％-15％ DURO-TAK 387-2287 70％-80％ DURO-TAK 87-4098 0-5％ methacrylate alkyl ester copolymer 1％-3％ Isopropyl myristate 2％-4％ polyethylene glycol 0-2％ lactic acid 1％-3％ Oleic acid 1％-2％ dimethylacetamide 1％-2％ .

[0040] In a more preferred embodiment of the present invention, when the adhesive matrix is ​​selected from synthetic rubber, styrene-isoprene-styrene block copolymer is preferred. Furthermore, it also includes tackifier and softener together as adhesive matrix, and the content of the adhesive matrix layer is 75-95% by weight, more preferably 80-90% based on the total weight of the adhesive matrix layer.

[0041] In a more preferred embodiment of the present invention, the weight percentage of synthetic rubber is 10-30%, the weight percentage of tackifier is 30-65%, and the weight percentage of softener is 10-30%, based on the weight of the adhesive matrix.

[0042] In a more preferred embodiment of the present invention, the softener is selected from one or more of paraffin oils, silicone oils, higher fatty acids, and vegetable oils, preferably one or more of liquid paraffin, white oil, naphthenic oil, squalane, squalene, silicone oil, petrolatum, or lanolin; more preferably liquid paraffin.

[0043] In a more preferred embodiment of the present invention, the tackifier is selected from one or more of terpene resin, petroleum resin, hydrogenated rosin glycerol ester, alicyclic saturated hydrocarbon resin, high molecular weight polyisobutylene, and low molecular weight polyisobutylene; preferably, it is selected from one or more of hydrogenated rosin glycerol ester, alicyclic saturated hydrocarbon resin, high molecular weight polyisobutylene, and low molecular weight polyisobutylene.

[0044] In a more preferred embodiment of the present invention, based on the total weight of the adhesive matrix layer, agomelatine accounts for 5-15% by weight, the adhesive matrix accounts for 75%-87% by weight, the penetration enhancer accounts for 2-10% by weight, and the antioxidant accounts for 0-2% by weight; more preferably, based on the total weight of the adhesive matrix layer, agomelatine accounts for 10-15% by weight, the adhesive accounts for 75%-90% by weight, the penetration enhancer accounts for 2-8% by weight, and the antioxidant accounts for 1-2% by weight.

[0045] In a more preferred embodiment of the invention, when the adhesive matrix is ​​selected from a combination of silicone and acrylic, more preferably, based on the total weight of the adhesive matrix layer, agomelatine accounts for 5-15% by weight, the adhesive accounts for 85%-95% by weight, and the penetration enhancer accounts for 1-3%.

[0046] In a more preferred embodiment of the invention, agomelatine is contained in the adhesive matrix layer in a dissolved state.

[0047] The adhesive backing layer used in this invention is used to support the adhesive matrix layer and has a certain degree of sealing and flexibility. It can be selected from polypropylene, polyethylene, polyvinyl chloride, polyethylene terephthalate, composite aluminum foil, polyester, and non-woven composite PE film.

[0048] The protective layer material of the patch can be selected from polyethylene, polyethylene terephthalate, polypropylene, polystyrene, polycarbonate or fluorine-containing materials, such as silicone-treated polyethylene terephthalate, which have been treated with paraffin or silicone release agents.

[0049] The patch of the present invention can be cut into different sizes according to different clinical needs, such as 45mm×45mm, 55mm×55mm, 65mm×65mm, etc. Correspondingly, due to the different sizes of the patch, the content of the patch is also different. The drug content of the patch is 5% to 15%, and more preferably 8% to 12%.

[0050] Through extensive research, the inventors of this application discovered that a patch prepared by incorporating agomelatine at a supersaturated concentration into a pressure-sensitive adhesive layer achieves the following results: it releases a therapeutically effective amount of drug to the patient, the release and controllability of the drug, and the ability to achieve the desired formulation release. Furthermore, it possesses the necessary physical properties, such as adhesion and peel strength, and the preparation method is simple. In addition, the agomelatine patch of this invention exhibits excellent safety. Detailed Implementation

[0051] To better illustrate the specific implementation schemes and effects of the present invention, further explanation will be provided below in conjunction with specific embodiments.

[0052] Example 1

[0053] Adhesive matrix layer formulation composition:

[0054]

[0055]

[0056] Preparation method: Dissolve the prescribed amounts of DURO-TAK 387-2287, DURO-TAK 87-4098, isopropyl myristate, dimethylacetamide, lactic acid, and ethyl acetate by stirring. Add agomelatine and stir until homogeneous. Apply the resulting medicated ointment evenly to the protective layer, dry to remove the solvent, and then adhere it to the backing layer used as the preparation. Cut it into the set size and shape to obtain the external patch of the present invention.

[0057] Example 2

[0058] Adhesive matrix layer formulation composition:

[0059]

[0060] Preparation method: Dissolve the prescribed amounts of DURO-TAK 387-2287, DURO-TAK 87-4098, isopropyl myristate, dimethylacetamide, lactic acid, and ethyl acetate by stirring. Add agomelatine and stir until homogeneous. Apply the resulting medicated ointment evenly to the protective layer, dry to remove the solvent, and then adhere it to the backing layer used as the preparation. Cut it into the set size and shape to obtain the external patch of the present invention.

[0061] Example 3

[0062] Adhesive matrix layer formulation composition:

[0063]

[0064]

[0065] Preparation method: Dissolve the prescribed amounts of DURO-TAK 387-2287, DURO-TAK 87-4098, isopropyl myristate, dimethylacetamide, lactic acid, and ethyl acetate by stirring. Add agomelatine and stir until homogeneous. Apply the resulting medicated ointment evenly to the protective layer, dry to remove the solvent, and then adhere it to the backing layer used as the preparation. Cut it into the set size and shape to obtain the external patch of the present invention.

[0066] Example 4

[0067] Adhesive matrix layer formulation composition:

[0068]

[0069] Preparation method: Dissolve the prescribed amounts of DURO-TAK 387-2516, DURO-TAK 87-2074, isopropyl myristate, dimethylacetamide, and lactic acid by stirring. Add agomelatine and stir until homogeneous. Apply the resulting medicated ointment evenly to the protective layer, dry to remove the solvent, and then adhere it to the backing layer. Cut it into the set size and shape to obtain the external patch of the present invention.

[0070] Example 5

[0071] Adhesive matrix layer formulation composition:

[0072]

[0073] Preparation method: Dissolve the prescribed amounts of DURO-TAK 387-2287, DURO-TAK 87-4098, isopropyl myristate, polyethylene glycol 400, and lactic acid by stirring. Add agomelatine and stir until homogeneous. Apply the resulting medicated ointment evenly to the protective layer, dry to remove the solvent, and then bond it to the backing layer used as the preparation. Cut it into the set size and shape to obtain the external patch of the present invention.

[0074] Example 6

[0075] Adhesive matrix layer formulation composition:

[0076]

[0077] Preparation method: Dissolve the prescribed amounts of DURO-TAK 387-2516, DURO-TAK 87-2074, isopropyl myristate, polyethylene glycol 400, and lactic acid by stirring. Add agomelatine and stir evenly. Apply the resulting medicated ointment evenly to the protective layer, dry to remove the solvent, and then adhere it to the backing layer. Cut it into the set size and shape to obtain the external patch of the present invention.

[0078] Example 7

[0079] Adhesive matrix layer formulation composition:

[0080]

[0081] Preparation method: Dissolve the prescribed amounts of DURO-TAK 387-2516, DURO-TAK 87-2074, d-limonene, lactic acid, Eutrapine E100 and ethyl acetate by stirring. Add agomelatine and stir until homogeneous. Coat the resulting medicated ointment evenly onto the protective layer, dry to remove the solvent, and then adhere it to the backing layer. Cut it into the set size and shape to obtain the external patch of the present invention.

[0082] Example 8

[0083] Adhesive matrix layer formulation composition:

[0084]

[0085] Preparation method: Dissolve the prescribed amounts of DURO-TAK 387-2516, DURO-TAK 87-2074, triglycerides, lactic acid, Eutrapine E100 and ethyl acetate by stirring. Add agomelatine and stir until homogeneous. Apply the resulting medicated ointment evenly to the protective layer, dry to remove the solvent, and then adhere it to the backing layer. Cut it into the set size and shape to obtain the topical patch of the present invention.

[0086] Example 9

[0087] Adhesive matrix layer formulation composition:

[0088]

[0089] Preparation method: Dissolve the prescribed amounts of DURO-TAK 387-2516, DURO-TAK 87-2074, dimethylacetamide, lactic acid, Eutrapine E100 and ethyl acetate by stirring. Add agomelatine and stir until homogeneous. Apply the resulting medicated ointment evenly to the protective layer, dry to remove the solvent, and then adhere it to the backing layer. Cut it into the set size and shape to obtain the external patch of the present invention.

[0090] Example 10

[0091] Adhesive matrix layer formulation composition:

[0092]

[0093] Preparation method: Dissolve the prescribed amounts of DURO-TAK 387-2516, DURO-TAK 87-2074, isopropyl myristate, lactic acid, Eutrapine E100 and ethyl acetate by stirring. Add agomelatine and stir until homogeneous. Apply the resulting medicated ointment evenly to the protective layer, dry to remove the solvent, and then adhere it to the backing layer. Cut it into the set size and shape to obtain the external patch of the present invention.

[0094] Example 11

[0095] Adhesive matrix layer formulation composition:

[0096]

[0097]

[0098] Preparation method: The prescribed amounts of SIS, alicyclic saturated hydrocarbon resin, hydrogenated rosin glycerol ester, a portion of liquid paraffin, polybutene, polyethylene glycol 6000, and butylated hydroxytoluene are heated and dissolved, and mixed evenly; the remaining liquid paraffin, isopropyl myristate, and isostearic acid are added to the above solution and mixed evenly; after the ointment cools down, the prescribed amount of agomelatine is added and stirred evenly; the resulting medicated ointment is evenly coated on the protective layer, adhered to the backing layer, and cut into the set size and shape to obtain the external patch of the present invention.

[0099] Example 12

[0100] materials Amount added (g) percentage(%) Agomelatin 12.5 5.0 SIS 46.75 18.7 Alicyclic saturated hydrocarbon resins 67.5 27.0 Hydrogenated rosin glycerides 25.0 10.0 Liquid paraffin 45.0 18.0 Low molecular weight polyisobutylene 25.0 10.0 Isopropyl myristate 4.5 1.8 Polyethylene glycol 6000 11.25 4.5 Isostearic acid 10.0 4.0 Butylated hydroxytoluene 2.5 1.0 Toluene (solvent, ultimately removed) 120.0 ——

[0101] Preparation method: The prescribed amounts of SIS, alicyclic saturated hydrocarbon resin, hydrogenated rosin glycerol ester, toluene, liquid paraffin, polybutene, polyethylene glycol 6000, and butylated hydroxytoluene are heated and dissolved, and mixed evenly; isopropyl myristate and isostearic acid are added to the above solution and mixed evenly; after the ointment cools down, the prescribed amount of agomelatine is added and stirred evenly; the resulting medicated ointment is evenly coated on the protective layer, dried to remove the solvent, and then adhered to the backing layer and cut into the set size and shape to obtain the external patch of the present invention.

[0102] Example 13

[0103]

[0104]

[0105] Preparation method: The prescribed amounts of SIS, hydrogenated rosin glycerol ester, liquid paraffin, high molecular weight polyisobutylene, low molecular weight polyisobutylene, and butylated hydroxytoluene are heated and dissolved, and mixed evenly; isopropyl myristate and isostearic acid are added to the above solution and mixed evenly; after the ointment cools down, the prescribed amount of agomelatine is added and stirred evenly; the resulting medicated ointment is evenly coated on the protective layer, adhered to the backing layer, and cut into the set size and shape to obtain the external patch of the present invention.

[0106] Example 14

[0107]

[0108] Preparation method: Dissolve the prescribed amounts of high molecular weight polyisobutylene, low molecular weight polyisobutylene, hydrogenated rosin glyceryl ester, cyclohexane and isopropyl myristate by stirring; add agomelatine and stir evenly; evenly coat the resulting medicated ointment onto the protective layer, adhere it to the backing layer, and cut it into the set size and shape to obtain the external patch of the present invention.

[0109] Example 15

[0110]

[0111]

[0112] Preparation method: Dissolve the prescribed amounts of high molecular weight polyisobutylene, low molecular weight polyisobutylene, hydrogenated rosin glyceryl ester, cyclohexane and isopropyl myristate by stirring; add agomelatine and stir evenly; evenly coat the resulting medicated ointment onto the protective layer, adhere it to the backing layer, and cut it into the set size and shape to obtain the external patch of the present invention.

[0113] Example 16

[0114] materials Amount added (g) percentage(%) Agomelatin 25 10.5 Dow Corning T4500 106.5 44.75 Dow Corning T4200 106.5 44.75 Heptane (solvent, eventually removed) 32.5 ——

[0115] Preparation method: Dissolve the prescribed amounts of Dow Corning T4500, Dow Corning T4200, and heptane by stirring. Add agomelatine and stir until uniform. Apply the resulting medicated ointment evenly to the protective layer, dry to remove the solvent, and then adhere it to the backing layer. Cut it into the set size and shape to obtain the external patch of the present invention.

[0116] Example 17

[0117] materials Amount added (g) percentage(%) Agomelatin 12.5 5.0 Dow Corning T4500 118.75 47.5 Dow Corning T4200 118.75 47.5 Heptane (solvent, eventually removed) 85 ——

[0118] Preparation method: Dissolve the prescribed amounts of Dow Corning T4500, Dow Corning T4200, and heptane by stirring. Add agomelatine and stir until uniform. Apply the resulting medicated ointment evenly to the protective layer, dry to remove the solvent, and then adhere it to the backing layer. Cut it into the set size and shape to obtain the external patch of the present invention.

[0119] Example 18

[0120]

[0121]

[0122] Preparation method: Dissolve the prescribed amounts of Dow Corning T4200, DURO-TAK 87-2196, and heptane by stirring. Add isopropyl myristate and agomelatine, stir until uniform, and then evenly coat the resulting medicated ointment onto the protective layer. After drying to remove the solvent, adhere it to the backing layer and cut it into the set size and shape to obtain the external patch of the present invention.

[0123] Example 1: Determination of Drug Content

[0124] Patches with different drug concentrations were prepared, and the crystallization on the patch surface was investigated, as well as the effect of concentration on drug release.

[0125] The results showed that when the drug content of the patch was 6%, 8%, and 10%, no drug crystals were precipitated on the surface of the patch, and even when the drug was in a supersaturated state in the adhesive layer, no crystals were precipitated.

[0126] Table 1. Effects of different drug concentrations on release

[0127]

[0128] Conclusion: Higher drug concentrations in transdermal patches result in faster drug release. Within the concentration range of this invention, the agomelatine patch achieves good drug release.

[0129] Experiment Example 2: Effect of Coating Thickness on Drug Release

[0130] Samples with the same concentration but different dry gel layer thicknesses were prepared to investigate the effect of gel layer thickness on drug release.

[0131] The results showed that, at the same drug concentration, the drug release gradually prolonged with the increase of drug layer thickness, achieving a sustained-release effect.

[0132]

[0133] Experimental Example 3: Agomelatine Topical Patch Release Test and Skin Permeation Test

[0134] The release and skin penetration of agomelatine topical patches were evaluated using the following test methods, based on the agomelatine topical patches described in Examples 3, 4, and 11.

[0135] 1) Methods for release testing

[0136] According to the 2015 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 0931, Dissolution and Release Determination Method IV—Paddle Disk Method, using 900 mL of pH 6.8 phosphate buffer as the release medium and a rotation speed of 50 rpm, the transdermal patch was fixed on the mesh disc with the drug-containing side facing upwards, keeping it as flat as possible. The mesh disc was then placed horizontally under the dissolution vessel, parallel to the rotating surface of the paddle, with a distance of 25 mm ± 2 mm between them. The apparatus was started, and 10 mL samples were taken at 0.5 h, 1 h, 2 h, 4 h, 6 h, and 8 h to prepare the test solution. Approximately 10 mg of agomelatine reference standard was accurately weighed and placed in a 1000 mL volumetric flask. An appropriate amount of release medium was added, and the mixture was shaken to dissolve completely. Release medium was then added to the mark, and the mixture was shaken well to prepare the reference solution. 20 μL each of the reference solution and the test solution were accurately injected into the liquid chromatograph, and the chromatograms were recorded. Calculate the release amount of each tablet at different times.

[0137]

[0138]

[0139] 2) Skin permeability test method

[0140] Treatment of nude mouse skin: Two-week-old nude mice were euthanized by dislocation of the neck, the skin was peeled off, and subcutaneous fat was carefully removed. The skin was then refrigerated at -30°C for later use. Before use, the skin was thawed and washed with physiological saline.

[0141] Experimental method: Transdermal testing was conducted using a Franz transdermal diffusion cell at a water bath temperature of 32℃. The stirring speed was 300 rpm, and the transdermal area was 1.76 cm². 2 The receiving cell volume was 7 ml, and the receiving solution was a 20% ethanol-physiological saline solution. Patches of the samples from Examples 3, 4, and 11 were adhered to the stratum corneum of the skin, ensuring close contact between the dermis and the receiving medium. The patches were fixed to the receiving cell, and 5 mL samples were taken periodically, with blank receiving solution replenished at a constant temperature of 32°C. The samples were analyzed by high-performance liquid chromatography (HPLC).

[0142]

[0143] The results showed that the agomelatine topical patch prepared in this invention has a stable release rate and good permeability.

[0144] Experiment Example 4: Skin Irritation Test

[0145] 1. Experimental Method: Six rabbits were randomly divided into two groups: an intact skin group and a damaged skin group. Hair was removed from the backs of the animals 24 hours before drug administration. Five patches each of the test substance (patch from Example 1) and the control substance (blank patch) were applied to the test substance area and control substance area (45cm) on the backs of the animals, respectively. 2 Apply the drug once daily for 7 consecutive days. Remove any residue with warm water and saline solution 24 hours after the last administration. Observe the erythema and edema at the application site 1, 24, 48, and 72 hours after drug removal, as well as the recovery time and duration of these changes. For each animal, evaluate the stimulus response and intensity according to the guidelines for preclinical research of new drugs.

[0146] 2. Test results: In the rabbit skin irritation test, no irritation reaction was observed in either the intact skin group or the damaged skin group after administration of this product.

[0147] 3. Conclusion: This product showed no irritation to the skin of rabbits.

[0148] Stability test results of Experiment Example 5

[0149] The patches from Examples 1-7 were subjected to accelerated testing (60°C, RH 75%), followed by a two-month stability test, and the residual drug content was determined. The results showed that, after accelerated testing and HPLC analysis, the drug content of the present invention showed minimal loss and no crystallization, indicating good stability of the agomelatine topical patch, making it safer for patients.

Claims

1. Agomelatine transdermal patch, characterized in that, It comprises (a) a backing layer, (b) an adhesive matrix layer and (c) a protective layer, wherein the adhesive matrix layer contains agomelatine and an adhesive matrix, wherein the adhesive matrix is ​​an acrylic pressure-sensitive adhesive, specifically selected from a combination of DURO-TAK 2287 and DURO-TAK 4098 or a combination of DURO-TAK 2516 and DURO-TAK 2074; In the adhesive matrix layer, based on the total weight of the adhesive matrix layer, the weight percentage of agomelatine is 10-15%, and the weight percentage of the adhesive matrix is ​​75-95%. Furthermore, based on the total weight of the adhesive matrix layer, the weight percentage of DURO-TAK 2287 is 70%-80%, the weight percentage of DURO-TAK 4098 is 5%-15%, the weight percentage of DURO-TAK 2516 is 70%-80%, and the weight percentage of DURO-TAK 2074 is 5%-15%.

2. The agomelatine transdermal patch according to claim 1, characterized in that, In the adhesive matrix layer, the weight percentage of agomelatine content is 10-12% based on the total weight of the adhesive matrix layer.

3. The agomelatine transdermal patch according to claim 1, characterized in that, In the adhesive matrix layer, the weight percentage of the adhesive matrix content is 80%-90% based on the total weight of the adhesive matrix layer.

4. The agomelatine transdermal patch according to claim 1, characterized in that, The thickness of the adhesive matrix layer is 40-65μm.

5. The agomelatine transdermal patch according to claim 1, characterized in that, The adhesive matrix layer also contains other pharmaceutically acceptable excipients selected from penetration enhancers and fillers, and the total weight percentage of other pharmaceutically acceptable excipients does not exceed 15% of the total weight of the adhesive matrix layer.

6. The agomelatine transdermal patch according to claim 5, characterized in that, The penetration enhancer is selected from one or more of oleic acid, lactic acid, polyethylene glycol, isopropyl myristate, and dimethylacetamide; its content is 2-6% by weight based on the total weight of the adhesive matrix layer.

7. The agomelatine transdermal patch according to claim 6, characterized in that, Based on the total weight of the adhesive matrix layer, agomelatine accounts for 10-15% by weight, acrylic pressure-sensitive adhesive accounts for 75%-85% by weight, isopropyl myristate accounts for 2%-4% by weight, polyethylene glycol accounts for 0-2% by weight, lactic acid accounts for 1%-3% by weight, oleic acid accounts for 1%-2% by weight, and dimethylacetamide accounts for 1%-2% by weight.

8. The agomelatine transdermal patch according to claim 6, characterized in that, The penetration enhancer is selected from isopropyl myristate, lactic acid, a two-component combination of isopropyl myristate and lactic acid, a two-component combination of triglyceride and lactic acid, a three-component combination of isopropyl myristate, lactic acid and dimethylacetamide, a three-component combination of isopropyl myristate, lactic acid and polyethylene glycol, a four-component combination of isopropyl myristate, oleic acid, lactic acid and dimethylacetamide, or a five-component combination of isopropyl myristate, oleic acid, lactic acid, polyethylene glycol and dimethylacetamide.

9. The agomelatine transdermal patch according to claim 1, characterized in that, The backing layer material is selected from polypropylene, polyethylene, polyvinyl chloride, polyethylene terephthalate, composite aluminum foil, polyester, and non-woven composite PE film; the protective layer material is selected from polyethylene, polypropylene, polystyrene, polycarbonate, or fluorine-containing materials treated with paraffin or organosilicon release agents.

10. The agomelatine transdermal patch according to claim 1, characterized in that, Agomelatine is contained in the adhesive matrix layer in a dissolved state.

11. The use of the agomelatine transdermal patch according to any one of claims 1-10 in the preparation of a drug for treating mental illnesses, wherein the mental illness refers to depression.

12. The application according to claim 11, characterized in that, The mental illness mentioned refers to severe depression.

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